A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate.
Nat Med 2019 Jan; 25(1):75-81
Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.
Caielli, Simone; Veiga, Diogo Troggian; Balasubramanian, Preetha; Athale, Shruti; Domic, Bojana; Murat, Elise; Banchereau, Romain; Xu, Zhaohui; Chandra, Manjari; Chung, Cheng-Han; Walters, Lynnette; Baisch, Jeanine; Wright, Tracey; Punaro, Marilynn; Nassi, Lorien; Stewart, Katie; Fuller, Julie; Ucar, Duygu; Ueno, Hideki; Zhou, Joseph; Banchereau, Jacques; and Pascual, Virginia, "A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate." (2019). Faculty Research 2019. 9.